This study examines the clinical and molecular effects of three well-known heritable disorders of connective tissue, Marfan syndrome, Ehlers-Danlos syndrome and Stickler syndrome. During previous years, a total of approximately 80 patients with each of the three specific diagnoses and 40 participants with an overlap disorder were seen in the NIH Clinical Center. Natural history data have been collected on all 280 participants, including ophthalmologic, otolaryngologic, echocardiography and rehabilitation medicine consultations. Our studies have documented newly recognized gastrointestinal complications of these disorders, and that chronic musculoskeletal pain is a significant complication of both EDS and Stickler syndrome. Echocardiography analysis of patients with Ehlers-Danlos syndrome demonstrated a 30% incidence of aortic root dilation in this group of patients. We have compared the Berlin and Gent nosologies for the Marfan syndrome in our population and examined the efficacy of screening for dural ectasia in the diagnosis of the Marfan syndrome. We have analyzed the prevalence of spinal and hip abnormlities in Stickler syndrome and their relationship to chronic pain. Our studies documented an increased risk of femoral head failure in children with Stickler syndrome. We have developed proposed diagnostic criteria for Stickler syndrome based on our clinical and molecular studies in this population. We have identified a previously undescribed connective tissue disorder with features resembling Marfan syndrome, Stickler syndrome and the Ehlers-Danlos syndrome. Chronic musculoskeletal pain is a serious complication of many of the hereditary disorders of connective tissue. This is particularly true in the Ehlers-Danlos syndrome. In collaboration with Dr. Shari Ling, we are about to embark on a clinical study to examine the connection between connective tissue disorders, chronic musculo-skeletal pain and fibromyalgia. During the coming year, we will also be looking at specific musculo-skeletal complications of aging in this population of patients, including the prevalence and severity of osteoporosis and osteoarthritis, as well as chronic musculo-skeletal pain as a generalized phenomenon.